Trial: A Clinical Study of MK-1084 With Target…

Trial Details

Sponsor: Merck Sharp & Dohme LLC (industry)

Phase: 3

Start date: July 16, 2025

Planned enrollment: 477

Trial ID: NCT06997497

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: MK-1084

Overview

MK-1084 is an investigational, oral, covalent inhibitor of KRAS G12C being developed by Merck (MSD). Early-phase clinical results (Phase 1, KANDLELIT-001; NCT05067283) have shown antitumor activity in KRAS G12C–mutated colorectal cancer (CRC) and non–small cell lung cancer (NSCLC). Randomized Phase 3 trials are ongoing in first-line KRAS G12C–mutated NSCLC (KANDLELIT-004; NCT06345729) and in first-line KRAS G12C–mutated CRC (KANDLELIT-012; NCT06997497). (merck.com)

Mechanism of action

MK-1084 is a selective, covalent KRAS G12C inhibitor that binds the inactive GDP-bound state of KRAS G12C. Its discovery leveraged structure-based design to create a macrocyclic scaffold optimized for potency and oral exposure; an X‑ray co‑crystal structure of MK-1084 bound to KRAS G12C (PDB 8S8C) corroborates target engagement. (pubs.acs.org)

Efficacy

Colorectal cancer (Phase 1, KANDLELIT‑001; ASCO 2025):
MK‑1084 monotherapy in previously treated CRC (n=53): confirmed ORR 38% (95% CI 25–52%); unconfirmed ORR 43%. (merck.com)
MK‑1084 + cetuximab in previously treated CRC (n=39): confirmed ORR 46% (95% CI 30–63%); unconfirmed ORR 56%. Reported DCR 92% and median DOR 10.8 months (follow‑up 9.2 months). (merck.com)
MK‑1084 + cetuximab + mFOLFOX6 in metastatic CRC with 0–1 prior lines (n=29): confirmed ORR 38% (95% CI 21–58%); unconfirmed ORR 66% (follow‑up 4.6 months). (merck.com)
Non–small cell lung cancer (Phase 1, KANDLELIT‑001; ASCO 2025):
MK‑1084 monotherapy in previously treated NSCLC (n=21): confirmed ORR 38% (95% CI 18–62%). (merck.com)
MK‑1084 + pembrolizumab in untreated metastatic NSCLC with PD‑L1 TPS ≥1% (n=69): confirmed ORR 77% (95% CI 65–86%). (merck.com)
MK‑1084 + pembrolizumab + chemotherapy (carboplatin/pemetrexed) in untreated metastatic NSCLC (n=40): confirmed ORR 53% (95% CI 36–69%). (merck.com)

Earlier dose‑escalation updates presented at ESMO 2023 and ESMO TAT 2024 also showed preliminary activity of MK‑1084 monotherapy and of MK‑1084 plus pembrolizumab in KRAS G12C–mutated tumors, supporting continued development. (oncologypro.esmo.org)

Safety

Across KANDLELIT‑001 arms presented at ASCO 2025, treatment‑related adverse events (TRAEs) occurred in 58% with MK‑1084 monotherapy, 94% with MK‑1084+pembrolizumab, 93% with MK‑1084+pembrolizumab+chemotherapy, 95% with MK‑1084+cetuximab, and 97% with MK‑1084+cetuximab+mFOLFOX6; the overall safety profile was characterized as manageable. Reported TRAEs in earlier updates included transaminase elevations and diarrhea with monotherapy/IO combinations, consistent with KRAS G12C inhibitor and checkpoint inhibitor class effects. (merck.com)

Ongoing/Planned studies

KANDLELIT‑004 (NCT06345729): Phase 3, randomized, double‑blind study of MK‑1084+pembrolizumab vs pembrolizumab in first‑line KRAS G12C–mutated, PD‑L1 TPS ≥50% NSCLC; coprimary endpoints PFS and OS (target n≈600). Status: recruiting (study start May 24, 2024). (merck.com)
KANDLELIT‑012 (NCT06997497): Phase 3, open‑label study of MK‑1084+cetuximab+mFOLFOX6 vs mFOLFOX6±bevacizumab in first‑line locally advanced unresectable or metastatic KRAS G12C–mutated CRC. Study start July 16, 2025. (ichgcp.net)

HealthScout AI Analysis

Goal: Evaluate whether adding the KRAS G12C inhibitor MK-1084 plus cetuximab to standard mFOLFOX6 improves outcomes and maintains acceptable safety compared with mFOLFOX6 with or without bevacizumab as first-line therapy for unresectable locally advanced or metastatic KRAS G12C–mutant colorectal cancer.

Patients: Adults with histologically confirmed colorectal adenocarcinoma that is unresectable Stage III or Stage IV per AJCC 8th edition and harbors a KRAS G12C mutation. Part 2 enrolls treatment-naive patients in the metastatic/unresectable setting. Key exclusions include active IBD requiring immunosuppression, significant uncontrolled cardiovascular/cerebrovascular disease, known DPD deficiency, active CNS metastases or leptomeningeal disease, recent other malignancies needing treatment, recent major surgery without recovery, active infections, and conditions precluding bevacizumab. Controlled HIV, HBV on antivirals with undetectable load, and cured/controlled HCV are allowed.

Design: Phase 3, randomized, open-label, multicenter study with two parts, allocating participants to experimental triplet therapy versus control. Approximately 477 participants will be randomized. Safety run-in in Part 1 assesses dose-limiting toxicities and tolerability, followed by efficacy-focused Part 2.

Treatments: Experimental arm: MK-1084 orally plus cetuximab every 2 weeks and mFOLFOX6 (oxaliplatin, leucovorin or levofolinate, and 5-fluorouracil) every 2 weeks until discontinuation criteria. Control arm: mFOLFOX6 every 2 weeks with optional bevacizumab per investigator discretion, until discontinuation criteria. MK-1084 is an investigational, selective covalent inhibitor of KRAS G12C that targets the GDP-loaded form via binding to the switch II pocket cysteine, aiming to lock KRAS G12C in an inactive state. Early-phase data in solid tumors, notably NSCLC, show single-agent activity (approximately 22% response rate) and enhanced responses when combined with pembrolizumab in first-line NSCLC, with a generally manageable safety profile characterized by elevated transaminases and diarrhea; grade 3–4 events were more frequent in combination settings. Cetuximab is an anti-EGFR antibody used off-label in RAS wild-type mCRC; here it is combined with KRAS G12C inhibition and chemotherapy to potentially overcome adaptive EGFR-mediated feedback signaling seen with KRAS G12C inhibitors.

Outcomes: Primary endpoints include dose-limiting toxicity during Part 1, overall safety and discontinuations due to adverse events in Part 1, and progression-free survival in Part 2. Key secondary endpoints are objective response rate by BICR per RECIST 1.1, overall survival, duration of response, comprehensive safety in Part 2, and patient-reported outcomes using EORTC QLQ-C30 (global health status/quality of life, physical and role functioning, appetite loss) and QLQ-CR29 bloating, including time to first deterioration analyses.

Burden on patient: Moderate. Participants receive biweekly intravenous chemotherapy and cetuximab infusions with associated infusion times, laboratory monitoring, and toxicity assessments, which are comparable to standard first-line mFOLFOX6 ± bevacizumab schedules. The addition of an oral daily MK-1084 and a biologic (cetuximab) may increase clinic time and dermatologic and electrolyte monitoring, particularly early in treatment. Part 1 may include closer safety assessments to capture dose-limiting toxicities. Imaging for response assessment is expected at regular intervals typical for metastatic CRC trials. No intensive pharmacokinetic schedules or mandatory serial biopsies are specified, suggesting burden above standard care primarily due to the extra infusion and monitoring rather than additional procedures or travel frequency beyond Q2W visits.

Last updated: Nov 2025

Eligibility

Show Criteria

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

* Has a histologically confirmed diagnosis of locally advanced unresectable or metastatic (unresectable Stage III or Stage IV as defined by American Joint Committee on Cancer \[AJCC\] eighth edition) colorectal adenocarcinoma

* Part 2 only: Has not received systemic anticancer therapy for locally advanced unresectable or metastatic colorectal cancer

* Tumor tissue demonstrates presence of a Kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutation

* Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART)

* Participants who are Hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy and have undetectable HBV viral load

* Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

* Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, chronic diarrhea)

* Has uncontrolled, significant cardiovascular disease or cerebrovascular disease

* Has known dihydropyrimidine dehydrogenase (DPD) deficiency

* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease

* Has received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization

* Has 1 or more conditions that, in the opinion of the investigator, make the participant ineligible for treatment with bevacizumab

* Has known additional malignancy that is progressing or has required active treatment within the past 3 years

* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease

* Has active infection requiring systemic therapy

* Has not adequately recovered from major surgery or have ongoing surgical complications

* Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease

Sites (52)

Sort by distance to:

Hospital Privado Universitario de Córdoba ( Site 0108)

Córdoba, X5016KEH, Argentina

No email / +543514688846

Status: Recruiting

Hospital Italiano de Buenos Aires ( Site 0102)

Ciudad Autonoma de Buenos Aires, Buenos Aires, C1199ABB, Argentina

No email / +5491155960279

Status: Recruiting

Fundacion Estudios Clinicos ( Site 0105)

Rosario, Santa Fe Province, S2000CEJ, Argentina

No email / +5493413168137

Status: Recruiting

Sunshine Coast University Hospital ( Site 0451)

Birtinya, Queensland, 4575, Australia

No email / +61752020000

Status: Recruiting

Fundação Faculdade Regional de Medicina de São José do Rio Preto ( Site 0159)

São José do Rio Preto, São Paulo, 15090-000, Brazil

No email / +55 17 3201-5054

Status: Recruiting

Anhui Provincial Cancer Hospital ( Site 0803)

Hefei, Anhui, 230031, China

No email / 0551-65327666

Status: Recruiting

The First Affiliated Hospital of Xiamen University ( Site 0806)

Xiamen, Fujian, 361003, China

No email / +86 13575559341

Status: Recruiting

Southern Medical University Nanfang Hospital ( Site 0812)

Guangzhou, Guangdong, 510515, China

No email / +86 02062786845

Status: Recruiting

Sun Yat-Sen University Cancer Center ( Site 0800)

Guangzhou, Guangdong, 510060, China

No email / +86 02087343565

Status: Recruiting

Jinan Central Hospital ( Site 0817)

Jinan, Shandong, 250013, China

No email / 0531-55739999

Status: Recruiting

Helsinki University Hospital - Comprehensive Cancer Center (HYKS - Syöpäkeskus) ( Site 1000)

Helsinki, Uusimaa, 00290, Finland

No email / +358504272703

Status: Recruiting

Katholisches Marienkrankenhaus gGmbH ( Site 1103)

Hamburg, 22087, Germany

No email / 00494025460

Status: Recruiting

Prince of Wales Hospital. ( Site 0500)

Hong Kong, Hong Kong

No email / + 852 3505 2211

Status: Recruiting

Queen Mary Hospital ( Site 0501)

Hong Kong, Hong Kong

No email / +852 2255 3838

Status: Recruiting

Hadassah Medical Center ( Site 1252)

Jerusalem, 9112001, Israel

No email / 02-6777111

Status: Recruiting

Rabin Medical Center ( Site 1251)

Petah Tikva, 4941492, Israel

No email / 03-9377589

Status: Recruiting

Rambam Health Care Campus ( Site 1253)

Haifa, 3109601, Israel

No email / +97247776234

Status: Recruiting

Sheba Medical Center ( Site 1254)

Ramat Gan, 5265601, Israel

No email / +97235303030

Status: Recruiting

National Cancer Center Hospital ( Site 0850)

Chūō, Tokyo, 104-0045, Japan

No email / +81-3-3542-2511

Status: Recruiting

Amphia Ziekenhuis, locatie Breda Molengracht ( Site 1352)

Breda, North Brabant, 4818 CK, Netherlands

No email / +31 76 5951006

Status: Recruiting

SC Radiotherapy Center Cluj SRL-Oncologie Medicala ( Site 1501)

Floresti/ Cluj, Cluj, 407280, Romania

No email / 021 9368

Status: Recruiting

Centrul de Oncologie Sfantul Nectarie-Medical ( Site 1500)

Craiova, Dolj, 200746, Romania

No email / +40 731 604 432

Status: Recruiting

Seoul National University Hospital ( Site 0706)

Seoul, 03080, South Korea

No email / +82-2-1588-5700

Status: Recruiting

National Cancer Center ( Site 0702)

Goyang-si, Kyonggi-do, 10408, South Korea

No email / +82319201737

Status: Recruiting

Seoul National University Bundang Hospital ( Site 0705)

Seongnam-si, Kyonggi-do, 13620, South Korea

No email / +8215883369

Status: Recruiting

Asan Medical Center ( Site 0707)

Songpa-gu, Seoul, 05505, South Korea

No email / 82-2-3010-3204

Status: Recruiting

Samsung Medical Center ( Site 0708)

Gangnam, Seoul, 06351, South Korea

No email / +82234100297

Status: Recruiting

Kyungpook National University Chilgok Hospital ( Site 0701)

Buk-Gu, Taegu-Kwangyokshi, 41404, South Korea

No email / +82532003011

Status: Recruiting

HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑON ( Site 1554)

Madrid, 28007, Spain

No email / +34914269325

Status: Recruiting

HOSPITAL UNIVERSITARIO VIRGEN DEL ROCIO ( Site 1556)

Seville, 41013, Spain

No email / +34 955 013 068

Status: Recruiting

Hospital Clinico San Carlos ( Site 1555)

Madrid, 28040, Spain

No email / 34913303000x484833

Status: Recruiting

Instituto Valenciano de Oncologia - IVO ( Site 1557)

Valencia, 46009, Spain

No email / 34961114000

Status: Recruiting

Institut Català d'Oncologia (ICO) - Badalona ( Site 1552)

Badalona, Barcelona, 08916, Spain

No email / 34 934 97 89 25

Status: Recruiting

Hospital Universitario Marqués de Valdecilla ( Site 1551)

Santander, Cantabria, 39008, Spain

No email / +34 942202525

Status: Recruiting

National Cheng Kung University Hospital ( Site 0754)

Tainan City, 704, Taiwan

No email / +88662353535

Status: Recruiting

Taipei Veterans General Hospital ( Site 0752)

Taipei, 112, Taiwan

No email / +886228712121

Status: Recruiting

Chang Gung Memorial Hospital - Linkou Branch ( Site 0753)

Taoyuan, Taoyuan, 333, Taiwan

No email / +88633281200

Status: Recruiting

LLC "MEDICAL CENTER DOBROBUT-CLINIC" ( Site 1703)

Kyiv, 03151, Ukraine

No email / +380671502987

Status: Recruiting

Medical Center "Universal Clinic "Oberig" of Limited Liability Company "Kapytal" ( Site 1704)

Kyiv, 03057, Ukraine

No email / +380669472333

Status: Recruiting

SI "National Institute of Surgery and Transplantology named after O. O. Shalimov" ( Site 1713)

Kyiv, 03126, Ukraine

No email / +380956017249

Status: Recruiting

MNE "Clinical Center of Oncology, Hematology, Transplantology and Palliative Care of CRC" ( Site 1706)

Cherkasy, Cherkasy Oblast, 18009, Ukraine

No email / +380472319418

Status: Recruiting

RMNE "Bukovyna Clinical Oncology Center" ( Site 1709)

Chernivtsi, Chernivetska Oblast, 58013, Ukraine

No email / 0443344770

Status: Recruiting

MNPE "Prykarpattia Clinical Oncology Center of Ivano-Frankivsk Regional Council" ( Site 1701)

Ivano-Frankivsk, Ivano-Frankivsk Oblast, 76018, Ukraine

No email / +380966059053

Status: Recruiting

CNE "Regional Clinical Oncology Center of the Kirovohrad Regional Council" ( Site 1702)

Kropyvnytskyi, Kirovohrad Oblast, 25011, Ukraine

No email / +380508427973

Status: Recruiting

MNPE LTMU Multidisc. Clin. Hosp. of Emerg. and Intens. Care ( Site 1708)

Lviv, Lviv Oblast, 79059, Ukraine

No email / +380977453295

Status: Recruiting

MNE "Central City Hospital" ( Site 1711)

Rivne, Rivne Oblast, 33017, Ukraine

No email / +380508266088

Status: Recruiting

ME "Volyn Regional Clinical Hospital" of the VRC ( Site 1712)

Lutsk, Volyn Oblast, +380332773100, Ukraine

No email / 380503782998

Status: Recruiting

Uzhgorod Central City Clinical Hospital ( Site 1700)

Uzhhorod, Zakarpattia Oblast, 88000, Ukraine

No email / +380953274431

Status: Recruiting

Orlando Health Cancer Institute ( Site 0065)

Orlando, Florida, 32806, United States

No email / 321-841-6780

Status: Recruiting

Norton Cancer Institute, Audubon Hospital Campus ( Site 0054)

Louisville, Kentucky, 40217, United States

No email / 502-636-7845

Status: Recruiting

Renown Regional Medical Center ( Site 0056)

Reno, Nevada, 89502, United States

No email / 775-982-4000

Status: Recruiting

Miami Valley Hospital South ( Site 0075)

Centerville, Ohio, 45459, United States

No email / 937-438-2400

Status: Recruiting

Trial Details

Show Summary from Sponsor

More details:

Investigational Drug AI Analysis

Show for: MK-1084

Overview

Mechanism of action

Efficacy

Safety

Ongoing/Planned studies

Further reading

HealthScout AI Analysis

Eligibility

Show Criteria

Sites (52)

Hospital Privado Universitario de Córdoba ( Site 0108)

Hospital Italiano de Buenos Aires ( Site 0102)

Fundacion Estudios Clinicos ( Site 0105)

Sunshine Coast University Hospital ( Site 0451)

Fundação Faculdade Regional de Medicina de São José do Rio Preto ( Site 0159)

Anhui Provincial Cancer Hospital ( Site 0803)

The First Affiliated Hospital of Xiamen University ( Site 0806)

Southern Medical University Nanfang Hospital ( Site 0812)

Sun Yat-Sen University Cancer Center ( Site 0800)

Jinan Central Hospital ( Site 0817)

Helsinki University Hospital - Comprehensive Cancer Center (HYKS - Syöpäkeskus) ( Site 1000)

Katholisches Marienkrankenhaus gGmbH ( Site 1103)

Prince of Wales Hospital. ( Site 0500)

Queen Mary Hospital ( Site 0501)

Hadassah Medical Center ( Site 1252)

Rabin Medical Center ( Site 1251)

Rambam Health Care Campus ( Site 1253)

Sheba Medical Center ( Site 1254)

National Cancer Center Hospital ( Site 0850)

Amphia Ziekenhuis, locatie Breda Molengracht ( Site 1352)

SC Radiotherapy Center Cluj SRL-Oncologie Medicala ( Site 1501)

Centrul de Oncologie Sfantul Nectarie-Medical ( Site 1500)

Seoul National University Hospital ( Site 0706)

National Cancer Center ( Site 0702)

Seoul National University Bundang Hospital ( Site 0705)

Asan Medical Center ( Site 0707)

Samsung Medical Center ( Site 0708)

Kyungpook National University Chilgok Hospital ( Site 0701)

HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑON ( Site 1554)

HOSPITAL UNIVERSITARIO VIRGEN DEL ROCIO ( Site 1556)

Hospital Clinico San Carlos ( Site 1555)

Instituto Valenciano de Oncologia - IVO ( Site 1557)

Institut Català d'Oncologia (ICO) - Badalona ( Site 1552)

Hospital Universitario Marqués de Valdecilla ( Site 1551)

National Cheng Kung University Hospital ( Site 0754)

Taipei Veterans General Hospital ( Site 0752)

Chang Gung Memorial Hospital - Linkou Branch ( Site 0753)

LLC "MEDICAL CENTER DOBROBUT-CLINIC" ( Site 1703)

Medical Center "Universal Clinic "Oberig" of Limited Liability Company "Kapytal" ( Site 1704)

SI "National Institute of Surgery and Transplantology named after O. O. Shalimov" ( Site 1713)

MNE "Clinical Center of Oncology, Hematology, Transplantology and Palliative Care of CRC" ( Site 1706)

RMNE "Bukovyna Clinical Oncology Center" ( Site 1709)

MNPE "Prykarpattia Clinical Oncology Center of Ivano-Frankivsk Regional Council" ( Site 1701)

CNE "Regional Clinical Oncology Center of the Kirovohrad Regional Council" ( Site 1702)

MNPE LTMU Multidisc. Clin. Hosp. of Emerg. and Intens. Care ( Site 1708)

MNE "Central City Hospital" ( Site 1711)

ME "Volyn Regional Clinical Hospital" of the VRC ( Site 1712)

Uzhgorod Central City Clinical Hospital ( Site 1700)

Orlando Health Cancer Institute ( Site 0065)

Norton Cancer Institute, Audubon Hospital Campus ( Site 0054)

Renown Regional Medical Center ( Site 0056)

Miami Valley Hospital South ( Site 0075)